Biography
My group works in what is now called chemical biology. Starting from an interest in natural products, we are trying to answer questions involving chemical ecology (what organisms make unusual natural products and why?), biosynthesis (how is a natural product made?), mechanism of action (what is the macromolecular target of a biologically active natural product?), structural biology (what is the three-dimensional structure of a natural product bound to its macromolecular target?), and structure-based drug design (how could an even better ligand for a macromolecular target be made?). Figure 1 shows several aspects of this work. In the center is a ball-and-stick representation of the natural product rapamycin, originally isolated because of its antifungal activity from soil microorganism found on Easter Island. When a related compound, FK506, was shown to be a potent immunosuppressive agent, rapamycin was reinvestigated and found to be an equally powerful cell cycle arrest agent. Currently, rapamycin is being investigated for possible use to treat cancer and to prevent the rejection of transplanted organs.
Rapamycin works by binding tightly to (FKBP) FK506 binding protein. In figure 1 the ribbon structure on the right is FKBP. The structure of the FKBP-rapamycin complex was described by our group in 1991. Rapamycin does not simply inhibit FKBP; the FKBP-rapamycin complex binds to and inhibits another protein called (FRAP) FKBP-rapamycin associated protein. In 1996 we described the structure (fig. 1), which shows how rapamycin simultaneously binds two different proteins, FKBP and FRAP, by occupying two very different binding pockets. Close relatives of the FRAP protein are involved in cell cycle progression and repair, and defects in these proteins can lead to diseases such as cancer. Rapamycin's unusual mechanism of action, its ability to dimerize two different proteins, has inspired the design of partially synthetic analogs that can be used to control cellular processes. Part of our ongoing research involves improving the design of such cellular control agents.
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